Bortezomib, chemically 3-methyl-1(R)-[N-(pyrazin-2-ylcarbonyl)-L-phenylalanyl-amino]-butylboronic acid of the formula (1)

is a pharmaceutically active compound used in treatment various tumors. Bortezomib is a selective proteasome inhibitor Inhibition of proteasome by bortezomib prevents the degradation of intracellular proteins, affecting multiple signalling cascades within cells leading to cell death and tumor growth inhibition.
Structurally, bortezomib is a boronated dipeptidic compound comprising L-leucine and L-phenylalanine moieties. Therefore, it comprises two chiral carbons and the molecule has rigid spatial orientation thus being a single diastereomer. It may form acid addition salts.
In solid state, bortezomib is present in trimeric boroxine form. Various crystalline polymorphs of bortezomib have been described in the literature.
Pharmaceutical compositions currently in medical use and sold, e.g., under the trade name Velcade comprise a sterile lyophilized mixture of bortezomib with mannitol, which excipient also reacts with bortezomib during lyophilization process upon formation a mannitol boronic ester.
Bortezomib has been first disclosed in WO 96/13266. The mannitol esters of bortezomib have been disclosed in WO 2002/059130, the trimeric form of bortezomib has been disclosed in WO 2002/059131.
As bortezomib is a dipeptide compound consisting of pyrazin-2-yl carboxylic acid (A), L-phenylalanine (B) and (R)-1-amino-3-methylbutylboronic acid (C) moieties, its structure may be generally denoted as

and its synthesis follows basic approaches in making peptides. Peptides are commonly prepared by coupling the acidic and aminic parts of corresponding amino acids using a coupling agent. In case of dipeptides, two possible routes shown below (approaches AB+C and A+BC, resp.) are principally applicable (necessary NH- or OH-protection excluded):

In each of four above steps indicated by an arrow, a coupling agent (“CA”) is necessary for performing the peptide-forming reaction.
In the basic patent family (WO 96/13266, EP 788360, U.S. Pat. No. 5,780,454 and others), no process of making bortezomib (denoted there as MG-341) is explicitly exemplified. As follows from the description, bortezomib may be probably prepared using a procedure starting with coupling of (1R)—(S)-pinanediol-1-amino-3-methylbutane-1-boronate of formula (2) with appropriate N-protected (pref. with Boc group) phenylalanine compound of formula (3) (see the above A+BC approach and “Route I” in the Scheme 1 below). The originator has filed a later patent application WO 2005/097809 disclosing improvements of this basic route. This application is in fact the first specific disclosure of the Route I process.
Process according the Route II of the Scheme 1 below, i.e. that of converting the compound of formula (2) directly to a compound of formula (4) using a peptide synthon of formula (6) (see the above AB+C approach), has been disclosed in recent applications WO 2009/004350 (Pliva/Teva) and WO 2009/036281 (Dr. Reddy).
Both routes produce bortezomib via its B—OH protected precursor of formula (4). The OH-groups in the compound (4) are typically protected by a chiral (S)-pinanediol protective group and the removal of this group (by a transesterification reaction with 2-methylpropane-boronic acid in acidic environment, as disclosed in WO 2005/097809) represents the common last step in making bortezomib (1).
As indicated above, coupling agents are necessary for coupling carboxylic acids with amines in both basic routes leading to bortezomib. At present, classical coupling agents, such as TBTU ((O-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) and DCC (N,N′-dicyclohexylcarbodiimide) in combination with 1-hydroxybenztriazole, are used in the prior art processes for making bortezomib. Such coupling agents however exhibit many disadvantages in the coupling process and improvement in this respect is therefore desirable.
